Gene Expression Profiling of Early Hepatic Stellate Cell Activation Reveals a Role for Igfbp3 in Cell Migration

Mannaerts, Inge; Schroyen, Ben; Verhulst, Stefaan; Lommel, Leentje Van; Schuit, Frans; Nyssen, Marc; Grunsven, Leo A. van

doi:10.1371/journal.pone.0084071

Cited by 41 publications

(42 citation statements)

References 61 publications

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“…IGFBP3 and NTM were implicated in the maintenance of the qHSC phenotype. Consistent with previous observations, expression of IGFBP3 and NTM were strongly down‐regulated in alcohol‐activated hHSCs (vs. normal hHSCs). In turn, ADA2 , a growth factor for endothelial cells and a promoter of differentiation of M2 macrophages, was highly induced in ALD HSCs.…”

Section: Discussionsupporting

confidence: 92%

Primary Alcohol‐Activated Human and Mouse Hepatic Stellate Cells Share Similarities in Gene‐Expression Profiles

et al. 2020

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Alcoholic liver disease (ALD) is a leading cause of cirrhosis in the United States, which is characterized by extensive deposition of extracellular matrix proteins and formation of a fibrous scar. Hepatic stellate cells (HSCs) are the major source of collagen type 1 producing myofibroblasts in ALD fibrosis. However, the mechanism of alcohol‐induced activation of human and mouse HSCs is not fully understood. We compared the gene‐expression profiles of primary cultured human HSCs (hHSCs) isolated from patients with ALD (n = 3) or without underlying liver disease (n = 4) using RNA‐sequencing analysis. Furthermore, the gene‐expression profile of ALD hHSCs was compared with that of alcohol‐activated mHSCs (isolated from intragastric alcohol‐fed mice) or CCl4‐activated mouse HSCs (mHSCs). Comparative transcriptome analysis revealed that ALD hHSCs, in addition to alcohol‐activated and CCl4‐activated mHSCs, share the expression of common HSC activation (Col1a1 [collagen type I alpha 1 chain], Acta1 [actin alpha 1, skeletal muscle], PAI1 [plasminogen activator inhibitor‐1], TIMP1 [tissue inhibitor of metalloproteinase 1], and LOXL2 [lysyl oxidase homolog 2]), indicating that a common mechanism underlies the activation of human and mouse HSCs. Furthermore, alcohol‐activated mHSCs most closely recapitulate the gene‐expression profile of ALD hHSCs. We identified the genes that are similarly and uniquely up‐regulated in primary cultured alcohol‐activated hHSCs and freshly isolated mHSCs, which include CSF1R (macrophage colony‐stimulating factor 1 receptor), PLEK (pleckstrin), LAPTM5 (lysosmal‐associated transmembrane protein 5), CD74 (class I transactivator, the invariant chain), CD53, MMP9 (matrix metallopeptidase 9), CD14, CTSS (cathepsin S), TYROBP (TYRO protein tyrosine kinase‐binding protein), and ITGB2 (integrin beta‐2), and other genes (compared with CCl4‐activated mHSCs). Conclusion: We identified genes in alcohol‐activated mHSCs from intragastric alcohol‐fed mice that are largely consistent with the gene‐expression profile of primary cultured hHSCs from patients with ALD. These genes are unique to alcohol‐induced HSC activation in two species, and therefore may become targets or readout for antifibrotic therapy in experimental models of ALD.

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Section: Discussionsupporting

confidence: 92%

Primary Alcohol‐Activated Human and Mouse Hepatic Stellate Cells Share Similarities in Gene‐Expression Profiles

et al. 2020

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“…The mode of recruitment used in tissue regeneration is chemotaxis, which is directional migrationin response to a release of chemoattractants including GFs and chemokines (Vanden Berg‐Foels, ). Although IGFBP3 is reported to recruit endothelial precursor cells and hepatic stellate cells, the role of IGFBP3 on MSC homing is still unclear (Kielczewski et al, ; Mannaerts et al, ). In the present study, Transwell data suggested that exogenous IGFBP3 remarkably improved hBMSC migration in a dose‐dependent manner (Figure b).…”

Section: Discussionmentioning

confidence: 99%

“…Some studies have demonstrated that IGFBP-3 controls cell apoptosisand survival-related functions on cancer cells (Galluzzi et al, 2012;Johnson & Firth, 2014). In addition, IGFBP3 recruits a variety of resident cells toward injury sites, including hematopoietic stem cells/endothelial precursor cells and hepatic stellate cells (Chang et al, 2007;Kielczewski et al, 2009;Mannaerts et al, 2013). The role of IGFBP3 from hUCMSC-ECM on the recruitment of MSC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

IGFBP3 deposited in the human umbilical cord mesenchymal stem cell‐secreted extracellular matrix promotes bone formation

Deng

Luo

Hou

et al. 2018

Journal Cellular Physiology

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The extracellular matrix (ECM) contains rich biological cues for cell recruitment, proliferationm, and even differentiation. The osteoinductive potential of scaffolds could be enhanced through human bone marrow mesenchymal stem cell (hBMSC) directly depositing ECM on surface of scaffolds. However, the role and mechanism of human umbilical cord mesenchymal stem cells (hUCMSC)‐secreted ECM in bone formation remain unknown. We tested the osteoinductive properties of a hUCMSC‐secreted ECM construct (hUCMSC‐ECM) in a large femur defect of a severe combined immunodeficiency (SCID) mouse model. The hUCMSC‐ECM improved the colonization of endogenous MSCs and bone regeneration, similar to the hUCMSC‐seeded scaffold and superior to the scaffold substrate. Besides, the hUCMSC‐ECM enhanced the promigratory molecular expressions of the homing cells, including CCR2 and TβRI. Furthermore, the hUCMSC‐ECM increased the number of migrated MSCs by nearly 3.3 ± 0.1‐fold, relative to the scaffold substrate. As the most abundant cytokine deposited in the hUCMSC‐ECM, insulin‐like growth factor binding protein 3 (IGFBP3) promoted hBMSC migration in the TβRI/II‐ and CCR2‐dependent mechanisms. The hUCMSC‐ECM integrating shRNA‐mediated silencing of Igfbp3 that down‐regulated IGFBP3 expression by approximately 60%, reduced the number of migrated hBMSCs by 47%. In vivo, the hUCMSC‐ECM recruited 10‐fold more endogenous MSCs to initiate bone formation compared to the scaffold substrate. The knock‐down of Igfbp3 in the hUCMSC‐ECM inhibited nearly 60% of MSC homing and bone regeneration capacity. This research demonstrates that IGFBP3 is an important MSC homing molecule and the therapeutic potential of hUCMSC‐ECM in bone regeneration is enhanced by improving MSC homing in an IGFBP3‐dependent mechanism.

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“…In addition, the insulin‐like growth factor I (IGF‐I) was able to induce senescence in HSCs. In vitro studies using primary rat HSCs (Mannaerts et al, ; Sumida et al, ) and the hepatic stellate lineage LX‐2 (Nishizawa et al, ) demonstrated the IGF‐I effects, inducing an increase in senescence markers (p21 and p53), and in the number of HSC positive to β‐galactosidase associated with senescence (SA‐β‐gal) (Handayaningsih et al, ). In addition, in vivo analysis emphasizes the role of IGF‐I in senescence and in the reversion of the hepatic fibrosing process.…”

Section: Hsc Senescence: Another Cellular Process That Helps To Contrmentioning

confidence: 99%

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

Silva

Ramos

Moraes

2017

Cell Biology International

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Liver fibrosis is a pathophysiological process correlated with intense repair and cicatrization mechanisms in injured liver, and over the past few years, the characterization of the fine-tuning of molecular interconnections that support the development of liver fibrosis has been investigated. In this cellular process, the hepatic stellate cells (HSCs) support the organ fibrogenesis. The HSCs are found in two distinct morpho-physiological states: quiescent and activated. In normal liver, most HSCs are found in quiescent state, presenting a considerable amount of lipid droplets in the cytoplasm, while in injured liver, the activated phenotype of HSCs is a myofibroblast, that secrete extracellular matrix elements and contribute to the establishment of the fibrotic process. Studies on the molecular mechanisms by which HSCs try to restore their quiescent state have been performed; however, no effective treatment to reverse fibrosis has been so far prescribed. Therefore, the elucidation of the cellular and molecular mechanisms of apoptosis, senescence, and the cell reversion phenotype process from activate to quiescent state will certainly contribute to the development of effective therapies to treat hepatic fibrosis. In this context, this review aimed to address central elements of apoptosis, senescence, and reversal of HSC phenotype in the control of hepatic fibrogenesis, as a guide to future development of therapeutic strategies.

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Gene Expression Profiling of Early Hepatic Stellate Cell Activation Reveals a Role for Igfbp3 in Cell Migration

Cited by 41 publications

References 61 publications

Primary Alcohol‐Activated Human and Mouse Hepatic Stellate Cells Share Similarities in Gene‐Expression Profiles

Primary Alcohol‐Activated Human and Mouse Hepatic Stellate Cells Share Similarities in Gene‐Expression Profiles

IGFBP3 deposited in the human umbilical cord mesenchymal stem cell‐secreted extracellular matrix promotes bone formation

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

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